Attention-Deficit/Hyperactivity is a major disorder of childhood which often continues into the adult years. Patients with Attention-Deficit/Hyperactivity have difficulty concentrating and organizing their behavior. In addition, they are impulsive and easily distracted. Some display major hyperactivity while others outgrow or never show the motor symptoms. Attention-Deficit/Hyperactivity affects about 3.5 million children and adolescents in the United States, about half of whom retain attentional difficulties into adulthood (Cantwell and Baker, 1988). Attention-Deficit/Hyperactivity can result in low self-esteem, poor relationships with peers and adults, and inferior performance in school. These difficulties can lead to serious emotional problems, truancy, drug abuse and criminal behavior (Pelham and Murphy, 1986). Moreover, the symptoms of Attention-Deficit/Hyperactivity commonly accompany those of Conduct Disorder (inappropriate aggression) and Tourette's Syndrome (inappropriate movements). Many of these same symptoms of disinhibited, inappropriate behaviors are also observed in elderly, demented individuals (e.g., agitation, wandering, inappropriate aggression). These disinhibited behaviors pose a serious problem to nursing homes and other caregivers.
This spectrum of disinhibited behaviors may arise from a dysfunction of the prefrontal cortex (Arnsten, A. F. T., Steere, J. C., Hunt R. D., (1996). The contribution of alpha-2 noradrenergic mechanisms to prefrontal cortical cognitive function: Potential significance to Attention Deficit Hyperactivity Disorder. Arch. Gen. Psychiatry 53:448-455.). The prefrontal cortex projects to the brain's motor areas (striatum, motor cortices; Goldman-Rakic, P. S. et al., (1992) The Prefrontal Cortex and Internally Generated Motor Acts, Current Opinion Neurobiol. 2:830-835) and thus functions to guide behavior appropriately. In addition, the prefrontal cortex may perform this function for intellectual and affective behaviors. Degeneration of the prefrontal cortex may produce disinhibited behavior in elderly demented individuals, while altered development of these systems may lead to childhood disorders such as Attention-Deficit/Hyperactivity, Conduct Disorder, and Tourette's Syndrome.
The ventromedial/orbital PFC (vm/orbPFC) is thought to play an essential role in behavioral calming, and thus drugs which improve vm/orbPFC function may represent an important advance in pharmacological treatment for behavioral disorders. In particular, treatments that improve vm/orbPFC function may be able to calm behavior without inducing sedation. In contrast to the dorsolateral PFC (dlPFC) which is important for attention regulation, the vm/orbPFC is thought to be more involved in regulation of emotional behavior and suppression of inappropriate behaviors. Lesions of vmPFC and/or orbital PFC in humans can produce immature behavior, lack of restraint, and increased motor activity (e.g. Blumer & Benson, 1975); Luria, 1966; Miller, 1992; Stuss et al., 1992). In monkeys, lesions localized to the ventral surface of the PFC have also been shown to produce locomotor hyperactivity (Ruch & Shenkin, 1943), hyper-reactivity to environmental stimulation, and altered aggression (Butter et al., 1970). These cortical areas have strong reciprocal connections with the amygdala (e.g. Morecraft et al., 1992), providing an opportunity to regulate the expression of aggressive and emotional behavior. Lesions of the vm/orbPFC impair reversal of object or spatial discrimination problems without altering original acquisition performance (Dias et al., 1996; Iversen & Mishkin, 1970; McEnancy & Butter, 1969; Mishkin et al., 1969; Oscar-Berman, 1978; Ridley et al., 1993). Impaired reversal performance is especially persistent following orbital PFC lesions (Butter, 1969; Iversen & Mishkin, 1970). Importantly, monkeys with orbital lesions are also disproportionately impaired in suppressing a response to a preferred stimulus independent of baiting conditions produced by the experimenter (Mishkin, 1964). Aged monkeys are also impaired on reversal, but not acquisition of discrimination problems, consistent with orbital PFC dysfunction with age (Bartus et al., 1979; Rapp, 1990).
Because recent research efforts have focused almost exclusively on developing treatments for the memory problems of dementia, there have been few new treatments for this spectrum of disorders. This focus has resulted in little research directed to the disorders of childhood. Attention-Deficit/Hyperactivity is usually treated with methylphenidate (Ritalin.TM. commercially available from Ciba Pharmaceutical), an amphetamine-like compound which is helpful for many patients (Hunt et al., 1991). However, methylphenidate has many deleterious side-effects including insomnia, appetite suppression, irritability, attentional "sticking", perseverative thoughts, increased aggression, and stunted growth (Hunt, R. D. (1988) Attention Deficit Disorder: Diagnosis, Assessment and Treatment. In Handbook of Clinical Assessment of Children and Adolescents--A Biopsychosocial Approach. C. Kestenbaum and D. Williams (eds.), pp. 519-561; McBurnett et al., 1991; Tannock and Schachar, 1992). Moreover, methylphenidate is contraindicated in patients with Conduct Disorder or Tourette's Syndrome because it can aggravate aggression and tics. Because many patients cannot tolerate methylphenidate, or find it only partially effective, alternative medications would be beneficial.
One alternative treatment for behavioral disorders has been the alpha-2 adrenergic agonist, clonidine (Hunt, R. D. et al., (1985) Clonidine Benefits Children with Attention Deficit Disorder and Hyperactivity: Report of a Double-Blind Placebo-Controlled Crossover Study, J. Amer. Acad. Child Psych., 24(5):617-629; 1986). Clonidine is particularly useful in Attention-Deficit/Hyperactivity patients who are very aggressive and/or highly aroused (Hunt, R. D. et al., (1990) Clonidine in Child and Adolescent Psychiatry, J. Child & Adol. Psychopharm., 1:87-101). However, it also has significant adverse side effects, including hypotension, "withdrawal" effects due to its short half life, and excessive sedation (ibid). It has been commonly assumed that the sedative action of clonidine is responsible for its beneficial effects in Attention-Deficit/Hyperactivity patients. It was presumed that clonidine attenuates noradrenergic tone, thereby decreasing arousal to near optimal levels (ibid). It was also presumed that clonidine improved Tourette's syndrome by a similar mechanism (Leckman, J. F. et al., (1989) Clonidine Treatment of Gilles de la Tourette Syndrome, Arch. Gen. Psychiatry, 48 324-328). Thus, even though the sedation itself often interfered with academic performance and other activities, the sedative side effects of clonidine treatment were thought to be essential for the beneficial effects of the drug.
Guanfacine, another alpha -2 adrenergic agonist, is less sedating than clonidine in monkeys (Arnsten, A. F. T. et al. (1988) The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: Evidence for alpha-2 receptor subtypes, J. Neurosci., 8: 4287-4298) and in humans (Kugler, J. et al., (1980) Differences in Psychic Performance with Guanfacine and Clonidine in Normotensive Subjects, Br. J. Clin. Pharmacol. 99:803-809). However, because clonidine was presumed to have its beneficial effects through its sedating actions, guanfacine was assumed to be less effective than clonidine in treating Attention-Deficit/Hyperactivity and related disorders. Very low doses of guanfacine (e.g. 0.00001-0.001 mg/kg) or moderate does of clonidine (about 0.01-0.05 mg/kg) improve working memory performance in aged monkeys without hypotensive or sedative side effects (Arnsten, A. F. T. et al., U.S. Pat. No. 4,847,300 which is incorporated herein by reference; Arnsten, A. F. T. et al., (1985) Alpha-2 adrenergic mechanisms in prefrontal cortex associated with cognitive decline in aged non-human primates, Science, 230:1273-1276; Arnsten, A. F. T. et al., (1988) The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: Evidence for alpha-2 receptor subtypes, J. Neurosci., 8:4287-4298). In addition, very low doses (0.000011-0.0011 mg/kg) of guanfacine enhanced working memory and attention regulation in aged monkeys (Arnsten, A. F. T. et al., (1992) Alpha-2 adrenergic agonists decrease distractibility in aged monkeys performing a delayed response task, Psychopharm. 108:159-169). The beneficial effects of guanfacine were particularly evident under conditions where distracting stimuli were present (ibid).
Lofexidine (2-{.alpha.-(2,6-dichlorphenoxy)-ethyl}-AE.sup.2 -imidazoline) is an investigational .alpha.-2-adrenergic agonist which is an antihypertensive similar to clonidine. Animal studies have shown that lofexidine lowers blood pressure (Burke J T, Koch-Weser J (1977) Lofexidine, a new centrally acting antihypertensive. Clin Pharmacol Ther 21: 99-100; Timmerman PBNWN, van Zweitan PA (1981). Correlations between central and hypotension and peripheral hypertensive effects of structuraly dissimilar alpha-adrenoreceptor agonists. Life Sci 28: 653-660; Graf E, Doppelfeld I S, Prop G (1982) Animal experiments on the cardiovascular effects of lofexidine. Arzneimittel-Forschung 32: 941-955), and some animal studies have shown that lofexidine may be less sedating than clonidine (Graf E, Sieck A, Wenzl H and Winkelmann J (1982) Animal experiments on the safety pharmacology of lofexidine. Arzneimittel-Forschung 32: 931-940). Clinical studies (Lopez, L M and Mehta J L (1984) AM. J. Cardiol 53: 787-790) have shown that lofexidine is significantly less potent than clonidine in decreasing blood pressure in hypertensive patients (lofexidine mean dose of 0.83 mg.+-.0.54 mg twice daily; clonidine mean dose 0.48.+-.0.29 mg twice daily). Lofexidine also produced fewer side effects than clonidine. In particular, clonidine produced significantly more dizziness and drowsiness than lofexidine (ibid; and Wilkins L H, Winternitz S R, Oparil S, Smith L R and Dustan H P (1981) Lofexidine and clonidine in moderate essential hypertension. Clin. Pharmacol. Ther. 30: 752-807). Lofexidine is also under investigational use for the treatment of opiate withdrawal (reviewed in Cox S and Alcorn R (1995) Lofexidine and opioid withdrawal. Lancet 345: 1385-1386). These studies indicate that lofexidine can decrease withdrawal signs with fewer sedative and hypotensive side effects than clonidine (Washton A M, Resnick R B, Geyer G (1983) Opiate withdrawal using lofexidine, a clonidine analogue with fewer side effects. J Clin Psychiatry 44: 335-337).
Because of the large patient population suffering from behavioral disinhibition and the deficiencies associated with existing therapies, a significant need exists for a method of treating behavioral disinhibition having a low incidence of adverse side-effects, especially sedation.